Doxycycline Treatment to Prevent Progressive Coronary Artery Dilation in Children With Kawasaki Disease

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2013 by Hawaii Pacific Health
Sponsor:
Information provided by (Responsible Party):
Andras Bratincsak, MD, PhD, Hawaii Pacific Health
ClinicalTrials.gov Identifier:
NCT01917721
First received: April 26, 2013
Last updated: August 8, 2013
Last verified: August 2013
  Purpose

Kawasaki disease (KD) affects infants and young children causing inflammation of the skin and blood vessels including the coronary arteries of the heart. Despite the currently available therapy, about one third of children develop enlargement of the coronary arteries that can lead to serious complications such as coronary artery stenosis, heart attack and even death.

Kawasaki disease is the most common heart disease in children in the USA and it is especially common among the children of Hawaii. Every year, 50-90 children are diagnosed with KD in Hawaii and unfortunately there is no medication available to successfully prevent coronary artery damage in a subset of cases.

During the first few weeks of the illness, cells of the immune system attack the coronary arteries and release a special substance (MMP) that is responsible for the coronary artery enlargement. There is a common antibiotic, doxycycline that can specifically block the action of this special substance (MMP). Research done on animals with KD showed that doxycycline was able to block this special substance and prevent enlargement of coronary arteries. Research in adults with enlargement of the main artery in their abdomen also showed that doxycycline may improve the outcome. Based on these studies doxycycline may be a promising therapy for children with KD, who develop enlargement of the coronary arteries.

The investigators' proposed research study will assess the usefulness of doxycycline in preventing the progressive enlargement of coronary arteries in children with KD. The investigators plan to perform a small (pilot) study to evaluate how good is doxycycline in preventing coronary artery enlargement. The investigators will treat 25 children with KD and enlarged coronary arteries for two weeks with doxycycline and assess the change in coronary arteries as well as the blood levels of the special substance (MMP). If doxycycline proves to be beneficial in this small study, the investigators are going to design a large research study involving multiple institutions on Hawaii and the mainland and will recruit more children to be certain about the value of the proposed treatment. The investigators' proposal may change the treatment protocol of KD and could present a possible treatment for children with enlarged coronary arteries preventing potentially devastating consequences.


Condition Intervention Phase
Kawasaki Disease
Coronary Aneurysm
Drug: Doxycycline
Drug: Standard care
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 2 Study to Assess the Efficacy and Safety of Doxycycline in Preventing Coronary Artery Aneurysm Formation and Progression

Resource links provided by NLM:


Further study details as provided by Hawaii Pacific Health:

Primary Outcome Measures:
  • Coronary artery diameter change [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    We will assess the change (+ or -) of coronary artery diameter from the beginning of doxycycline administration to the end of doxycycline administration and for an additional 2 months beyond that.


Secondary Outcome Measures:
  • Assess the change in MMP-9 level [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    We will draw blood samples before, during and after the administration of doxycyline to assess the effect on MMP-9 (matrix metalloproteinase 9).

  • Assess a change in TIMP level [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    We will draw blood samples before, during and after the administration of doxycyline to assess the effect on MMP-9 (matrix metalloproteinase 9) and TIMP (tissue inhibitor of matrix metalloproteinase).


Estimated Enrollment: 50
Study Start Date: October 2013
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Doxycycline
These patients will receive doxycycline at the acute phase of their disease
Drug: Doxycycline
The interventional arm of the study will receive doxycycline 4.4 mg/kg/day for 14 days besides receiveing standard care: IVIG and/or Remicade.
Other Name: doxycycline
Active Comparator: Standard care
The comparative arm of the study will receive standard care for Kawasaki disease, but not doxycycline
Drug: Standard care
Standard medical care will be provided to the comparative arm of the study administering IVIG and/or Remicade, but not doxycycline.
Other Name: IVIG and Remicade

Detailed Description:

This research study attempts to reveal whether coronary artery dilation in patients with Kawasaki disease refractory to standard therapy could be prevented using a matrix metalloproteinase inhibitor: doxycycline.

Hypothesis The investigators hypothesize that oral administration of doxycycline for two weeks during the acute phase of Kawasaki disease (KD) effectively blocks matrix metalloproteinase-9 (MMP-9) activity in the coronary arteries and therefore prevents the progression of coronary artery dilation and aneurysm formation in children with KD.

Rationale There is no specific treatment for children with KD, who develop coronary artery dilation or aneurysm. Based on the animal studies and adult trials showing beneficial effect of doxycycline on coronary artery dilation and abdominal aneurysms, this selective MMP-9 inhibitor offers a promising therapeutic strategy to prevent progressive coronary artery dilation in children with KD.

Specific aims

  1. Measure serum MMP-9 activity, tissue inhibitor of metalloproteinase 1 activity (TIMP-1), serum levels of degradation products due to MMP-9 activity (elastin and gelatin degradation products) before and after treatment with doxycycline in children with KD.
  2. Compare serum MMP-9 activity and degradation product levels of children receiving only standard therapy for KD (IVIG, infliximab) with children receiving standard therapy and doxycycline treatment.
  3. Measure the coronary artery diameters before and after doxycycline treatment in children with KD.
  4. Compare coronary artery measurements of children receiving only standard therapy for KD (IVIG, infliximab) with children receiving standard therapy and doxycycline treatment.
  5. Design a multi-center prospective randomized blinded placebo-controlled trial to assess the efficacy of doxycycline in preventing coronary artery dilation and aneurysm.
  Eligibility

Ages Eligible for Study:   1 Month to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Treatment arm: Patients aged 1 month to 18 years with confirmed KD will be included in the study if they meet the following criteria:

  1. Patients with dilation of the right or left anterior descending coronary artery beyond a z-score of +3 during the acute febrile phase of KD.
  2. Patients with aneurysms of the right or left main coronary arteries during the acute febrile phase of KD.
  3. Patients with refractory KD after initial treatment with IVIG and dilated coronary arteries on an echocardiogram during the first month of KD.

Comparison arm: Patients aged 1 month to 18 years with confirmed KD, who do not meet inclusion criteria to be included in the treatment group.

1.Patients with right or left anterior descending coronary artery measurements below a z-score of +3 during the acute febrile phase of KD.

Exclusion Criteria:

The following patients will be excluded from this study:

  1. Patients with clinically incomplete KD.
  2. Patients whose parents refuse to administer doxycycline.
  3. Patients with acute renal failure.
  4. Patients with chronic liver and kidney disease.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01917721

Contacts
Contact: Andras Bratincsak, Md PhD 808-942-7707 andrasb@kapiolani.org

Locations
United States, Hawaii
Kapiolani Medical Center for Women and Children Not yet recruiting
Honolulu, Hawaii, United States, 96826
Contact: Andras Bratincsak         
Principal Investigator: Andras Bratincsak, MD PhD         
Sub-Investigator: Marian Melish, MD         
Sponsors and Collaborators
Hawaii Pacific Health
Investigators
Principal Investigator: Andras Bratincsak, MD PhD Hawaii Pacific Health
  More Information

No publications provided

Responsible Party: Andras Bratincsak, MD, PhD, Clinical Assistant Professor, Hawaii Pacific Health
ClinicalTrials.gov Identifier: NCT01917721     History of Changes
Other Study ID Numbers: 2013-005
Study First Received: April 26, 2013
Last Updated: August 8, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Hawaii Pacific Health:
Kawasaki disease
doxycycline
coronary artery aneurysm

Additional relevant MeSH terms:
Aneurysm
Coronary Aneurysm
Mucocutaneous Lymph Node Syndrome
Cardiovascular Diseases
Coronary Disease
Heart Diseases
Lymphatic Diseases
Myocardial Ischemia
Skin Diseases
Skin Diseases, Vascular
Vascular Diseases
Vasculitis
Doxycycline
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014